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Journal ArticleDOI

Covalent nucleoside adducts of benzo[a]pyrene 7,8-diol 9,10-epoxides: structural reinvestigation and characterization of a novel adenosine adduct on the ribose moiety

01 Jan 1991-Journal of Organic Chemistry (American Chemical Society)-Vol. 56, Iss: 1, pp 20-29
About: This article is published in Journal of Organic Chemistry.The article was published on 1991-01-01. It has received 128 citations till now. The article focuses on the topics: Moiety & Diol.
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Journal ArticleDOI
TL;DR: The DNA damages caused through the reactive metabolites of PAH/HAC are described involving the DNA covalent binding to form stable or depurinating adducts, the formation of apurinic sites, and the oxidative damage.

829 citations


Cites background from "Covalent nucleoside adducts of benz..."

  • ...…primarily produced with dGuo except was trans for BgC (Szeliga et al., 1994, 1995) and trans equals cis for BcPh (Dipple et al., 1987), while with dAdo trans was preferred in all cases of PAH except for BaP where the adducts is in ~7/1 of cis/ trans ratio (Cheng et al., 1989; Sayer et al., 1991)....

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  • ..., 1987), while with dAdo trans was preferred in all cases of PAH except for BaP where the adducts is in ~7/1 of cis/ trans ratio (Cheng et al., 1989; Sayer et al., 1991)....

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Journal ArticleDOI
TL;DR: Findings indicate that the exceptional tumorigenic potency of B[c]Ph or related fjord region diol-epoxides may be attributed, at least in part, to slow repair of the stable base adducts deriving from the reaction of these compounds with DNA.
Abstract: The fjord region diol-epoxide metabolites of polycyclic aromatic hydrocarbons display stronger tumorigenic activities in rodent studies than comparable bay region diol-epoxides, but the molecular basis for this difference between fjord and bay region derivatives is not understood. Here we tested whether the variable effects of these genotoxic metabolites of polycyclic aromatic hydrocarbons may result from different DNA repair reactions. In particular, we compared the repairability of DNA adducts formed by bay region benzo[a]pyrene (B[a]P) diol-epoxides and the structurally similar but significantly more tumorigenic fjord region diol-epoxide metabolites of benzo[c]phenanthrene (B[c]Ph). For that purpose, we incorporated both types of polycyclic aromatic hydrocarbon adducts into known hot spot sites for carcinogen-induced proto-oncogene activation. Synthetic DNA substrates were assembled using a portion of human N-ras or H-ras that includes codon 61, and stereospecific B[a]P or B[c]Ph adducts were synthesized on adenine N6 at the second position of these two ras codon 61 sequences. DNA repair was determined by incubating the site-directed substrates in human cell extracts, followed by electrophoretic visualization of radiolabeled oligonucleotide excision products. These cell-free assays showed that all tested bay region B[a]P-N6-dA adducts are removed by the human nucleotide excision repair system, although excision efficiency varied with the particular stereochemical configuration of each B[a]P residue. In contrast, all fjord region B[c]Ph-N6-dA adducts located in the identical sequence context and with exactly the same stereochemical properties as the corresponding B[a]P lesions were refractory to the nucleotide excision repair process. These findings indicate that the exceptional tumorigenic potency of B[c]Ph or related fjord region diol-epoxides may be attributed, at least in part, to slow repair of the stable base adducts deriving from the reaction of these compounds with DNA.

119 citations


Cites background from "Covalent nucleoside adducts of benz..."

  • ...nucleosides with those documented in the literature (34, 35)....

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Journal ArticleDOI
TL;DR: Five lines of evidence are discussed suggesting that Hypothesis 2c can be correct for base substitution mutagenesis, which can each in principle rationalize many mutational results, including how the pattern of adduct Mutagenesis might be influenced by factors, such as DNA sequence context.
Abstract: Carcinogens are generally mutagens, which is understandable given that tumor cells grow uncontrollably because they have mutations in critical genes involved in growth control. Carcinogens often induce a complex pattern of mutations (e.g., GC-->TA, GC-->AT, etc.). These mutations are thought to be initiated when a DNA polymerase encounters a carcinogen-DNA adduct during replication. In principle, mutational complexity could be due to either a collection of different adducts each inducing a single kind of mutation (Hypothesis 1a), or a single adduct inducing different kinds of mutations (Hypothesis 1b). Examples of each are discussed. Regarding Hypothesis 1b, structural factors (e.g., DNA sequence context) and biological factors (e.g., differing DNA polymerases) that can affect the pattern of adduct mutagenesis are discussed. This raises the question: how do structural and biological factors influence the pattern of adduct mutagenesis. For structural factors, three possibilities are considered: (Hypothesis 2a) a single conformation of an adduct giving rise to multiple mutations -- dNTP insertion by DNA polymerase being influenced by (e.g.) the surrounding DNA sequence context; (Hypothesis 2b) a variation on this ("dislocation mutagenesis"); or (Hypothesis 2c) a single adduct adopting multiple conformations, each capable of giving a different pattern of mutations. Hypotheses 2a, 2b and 2c can each in principle rationalize many mutational results, including how the pattern of adduct mutagenesis might be influenced by factors, such as DNA sequence context. Five lines of evidence are discussed suggesting that Hypothesis 2c can be correct for base substitution mutagenesis. For example, previous work from our laboratory was interpreted to indicate that [+ta]-B[a]P-N(2)-dG in a 5'-CGG sequence context (G115) could be trapped in a conformation giving predominantly G-->T mutations, but heating caused the adduct to equilibrate to its thermodynamic mixture of conformations, leading to a decrease in the fraction of G-->T mutations. New work is described suggesting that [+ta]-B[a]P-N(2)-dG at G115 can also be trapped predominantly in the G-->A mutational conformation, from which equilibration can also occur, leading to an increase in the fraction of G-->T mutations. Evidence is also presented that the fraction of G-->T mutations is higher when [+ta]-B[a]P-N(2)-dG at G115 is in ss-DNA ( approximately 89%) vs. ds-DNA ( approximately 66%), a finding that can be rationalized if the mixture of adduct conformations is different in ss- and ds-DNA. In summary, the factors affecting adduct mutagenesis are reviewed and five lines of evidence that support one hypothesis (2c: adduct conformational complexity can cause adduct mutational complexity) are discussed.

118 citations

Book ChapterDOI
TL;DR: Although the solution chemistry of diol epoxides is now fairly well understood, a great deal remains to be elucidated regarding their reaction in the presence of DNA, and detailed conformational analysis of adducted DNA should prove to be extremely valuable in developing mechanistic models for the enzymatic processing of chemically altered DNA.
Abstract: Fifteen years ago, we proposed bay-region diol epoxides as the reactive metabolites responsible for the tumorigenic activity of polycyclic aromatic hydrocarbons (Jerina and Daly, 1976; Jerina et al, 1976; Jerina and Lehr, 1977) In the intervening period, extensive studies from several laboratories have provided substantial evidence that over a dozen hydrocarbons are activated by this pathway (Jerina et al, 1984; Lehr et al, 1985; Thakker et al, 1985) Examples have been forthcoming from a variety of structural types including benz- and dibenzanthracenes and acridines, benz- and dibenzpyrenes, chrysenes, and benzo[c]phenanthrene To date, there are no known examples of carcinogenic alternant polycyclic aromatic hydrocarbons for which a bay-region diol epoxide is not an ultimate carcinogen Although a number of mechanistically attractive alternatives to bay-region diol epoxides exist (Watabe et al, 1989; Cavalieri and Rogan, 1985; Miller et al, this volume), the extent of their contribution to the overall carcinogenicity of the hydrocarbons remains to be established

91 citations

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